Objective— Pathophysiological effects of the epidermal growth factor receptor (EGFR or ErbB1) include vascular remodeling. EGFR transactivation is proposed to contribute significantly to heterologous signaling and remodeling in vascular smooth muscle cells (VSMC). Methods and Results— We investigated the importance of EGFR in primary VSMC from aorta of mice with targeted deletion of the EGFR ( EGFR Δ/Δ VSMC →VSMC EGFR−/− and EGFR Δ/+ VSMC →VSMC EGFR+/− ) and the respective littermate controls ( EGFR +/+ VSMC →VSMC EGFR+/+ ) with respect to survival, pentose phosphate pathway activity, matrix homeostasis, extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylation, and Ca 2+ homeostasis. In VSMC EGFR−/− , epidermal growth factor–induced signaling was abolished; VSMC EGFR+/− showed an intermediate phenotype. EGFR deletion enhanced spontaneous cell death, reduced pentose phosphate pathway activity, disturbed cellular matrix homeostasis (collagen III and fibronectin), and abolished epidermal growth factor sensitivity. In VSMC EGFR−/− endothelin-1- or α 1 -adrenoceptor-induced ERK1/2 phosphorylation and the fraction of Ca 2+ responders were significantly reduced, whereas responsive cells showed a significantly stronger Ca 2+ signal. Oxidative stress (H 2 O 2 ) induced ERK1/2 activation in VSMC EGFR+/+ and VSMC EGFR+/− but not in VSMC EGFR−/− . The Ca 2+ signal was enhanced in VSMC EGFR−/− , similar to purinergic stimulation by ATP. Conclusion— In conclusion, EGFR was found to be important for basal VSMC homeostasis and ERK1/2 activation by the tested G-protein–coupled receptors or radical stress. Ca 2+ signaling was modulated by EGFR differentially with respect to the fraction of responders and magnitude of the signal. Thus, EGFR seems to be Janus-faced for VSMC biology.